TY - JOUR
T1 - Meta-analysis of gene-environment interaction
T2 - Joint estimation of SNP and SNP × environment regression coefficients
AU - Manning, Alisa K.
AU - LaValley, Michael
AU - Liu, Ching Ti
AU - Rice, Kenneth
AU - An, Ping
AU - Liu, Yongmei
AU - Miljkovic, Iva
AU - Rasmussen-Torvik, Laura
AU - Harris, Tamara B.
AU - Province, Michael A.
AU - Borecki, Ingrid B.
AU - Florez, Jose C.
AU - Meigs, James B.
AU - Cupples, L. Adrienne
AU - Dupuis, Josée
PY - 2011/1
Y1 - 2011/1
N2 - Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP × E) regression coefficients for use in gene-environment interaction studies. Methods: In testing SNP × E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP × E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP × E terms, and a test of homogeneity across samples. Results: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.
AB - Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP × E) regression coefficients for use in gene-environment interaction studies. Methods: In testing SNP × E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP × E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP × E terms, and a test of homogeneity across samples. Results: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.
KW - 2 degree of freedom meta-analysis
KW - Gene-environment interaction meta-analysis
KW - Joint meta-analysis
KW - PPARG
UR - http://www.scopus.com/inward/record.url?scp=78650332973&partnerID=8YFLogxK
U2 - 10.1002/gepi.20546
DO - 10.1002/gepi.20546
M3 - Article
C2 - 21181894
AN - SCOPUS:78650332973
SN - 0741-0395
VL - 35
SP - 11
EP - 18
JO - Genetic Epidemiology
JF - Genetic Epidemiology
IS - 1
ER -